Fungicidal pyridyl cyclopropane carboximides

ABSTRACT

Novel fungicidal pyridyl cyclopropane carboxamides having the general structural formula ##STR1## wherein R is selected from the group consisting of cycloalkyl, preferably cyclopropyl, hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, alkenyl, OR 1 , SR 1  and ##STR2## wherein n is 0-10, preferably 0-2, and R 1  is C 1  -C 4  alkyl, and R 2  is selected from the group consisting of halogen such as chlorine, fluorine and bromine, preferably chlorine, C 1  -C 3  alkoxy such as propoxyethoxy and methoxy, preferably methoxy and C 1  -C 3  haloalkoxy, R 3  is selected from the group consisting of hydrogen and methyl, X is --O or --S and Y is --O or --S; and fungicidally acceptable organic and inorganic salts thereof which are highly effective fungicides for use both as preventive and curative fungicides are disclosed herein.

This is a divisional, of application Ser. No. 036,545, U.S. Pat. No. 4,767,772 filed Apr. 15, 1987, which in turn is a continuation-in-part of application Ser. No. 029,103, filed Mar. 23, 1987, now abandoned, which in turn is a continuation of Ser. No. 859,169, filed May 2, 1986, now abandoned.

BACKGROUND OF THE INVENTION

Fungal infection of crops such as barley, rice, tomatoes, wheat, beans, roses, grapes and other agriculturally important crops can cause heavy losses in both quantity and quality of agricultural products. It is therefore extremely desirable to have means of preventing, controlling or eliminating fungal growth. Much preventive spraying with commerical fungicides is conducted to attempt to prevent the establishment and growth of fungi on agriculturally important crops. It would also be desirable to have a curative fungicide which, on detection of fungal infestation, can destroy the fungi and eliminate the deleterious effects by use of a post-infection curative spray.

SUMMARY OF THE INVENTION

Novel fungicidal pyridyl cyclopropane carboximides having the formula ##STR3## wherein R is selected from the group consisting of cycloalkyl, preferably cyclopropyl, hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, alkenyl, OR₁, SR₁ and ##STR4## wherein n is 0-10, preferably 0-2, and R₁ is C₁ -C₄ alkyl, R₂ is selected from the group consisting of halogen such as chlorine, fluorine and bromine, preferably chlorine, C₁ -C₃ alkoxy such as propoxyethoxy and methoxy, preferably methoxy and C₁ -C₃ haloalkoxy, R₃ is selected from the group consisting of hydrogen amd methyl, X is --O or --S and Y is --O or --S; and fungicidally acceptable organic and inorganic salts thereof which are highly effective fungicides for use both as preventive and curative fungicides are disclosed herein.

The term "fungicide" is used to mean a compound which controls fungal growth. "Controls" includes prevention, destruction and inhibition of fungal growth. The term "curative" is meant to refer to a post-infection application of a fungicide which establishes control of fungal infection and prevents development of deleterious effects of the fungi on the host crop.

DETAILED DESCRIPTION

The novel fungicidal compounds of this invention are pyridyl cyclopropane carboximides having the general formula ##STR5## wherein R is selected from the group consisting of cycloalkyl, preferably cyclopropyl, hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, alkenyl, OR₁, SR₁ and ##STR6## wherein n is 0-10, preferably 0-2, and R₁ is C₁ -C₄ alkyl, R₂ is selected from the group consisting of halogen such as chlorine, fluorine and bromine, preferably chlorine, C₁ -C₃ alkoxy such as propoxyethoxy and methoxy, preferably methoxy and C₁ -C₃ haloalkoxy, R₃ is selected from the group consisting of hydrogen and methyl, X is --O or --S and Y is --O or --S; and fungicidally acceptable organic and inorganic salts thereof which are highly effective fungicides for use both as preventive and curative fungicides are disclosed herein.

The compounds of this invention can be generally prepared by a multi-step reaction process. The first step comprises reacting a 2-methoxy-5-aminopyridine with cyclopropane carboxylic acid chloride in a polar solvent such as dichloromethane in a suitable reactor such as a glass reaction flask. It is desirable to maintain an acid scavenger such as pyridine in the reaction vessel. The reaction generally will proceed at room temperature but will operate at a temperature range from --30° to 80° C. The reaction should go to completion within 1 to 3 hours. The resulting intermediate product is recovered in a conventional manner by washing with an alkali solution such as NaOH and water, drying over conventional drying agents such as magnesium sulfate, washing with acetone, and crystallizing in hexane. The resulting N-(2-methoxy-5-pyridyl) cyclopropane carboxamide is then reacted with a properly substituted acid chloride in the presence of NaH or other strong base in an inert solvent such as tetrahydrofuran (THF). An alternate procedure is to react the N-(2-methoxy-5-pyridyl) cyclopropane carboxamide with a trialkylsilyl halide wherein the alkyl groups are C₁ -C₆ alkyl in the presence of an acid scavenger such as triethylamine to silylate the amide, followed by reaction with a properly substituted acid chloride. This silylamide is novel and has a general formula ##STR7## wherein R₂, R₃ and X are as defined above and R₄, R₅ and R₆ are C₁ -C₆ alkyl, preferably C₁ -C₄ alkyl, and most preferably methyl. This silylamide is useful to prepare novel fungicides of this invention. Also, a properly substituted 2-methoxy-5-pyridyl carboxamide may by silylated and then be treated with cyclopropane carboxylic acid chloride to give the desired product. Salts of the various pyridyl cyclopropane carboxamides can be conventionally prepared by reacting at least a molar amount of a Lewis acid with the carboxamide. Preferably the reaction is run in a solvent for the carboxamide. The prepared salt is recovered from the reaction mixture by conventional techniques.

Pyridyl carboxamides of the invention are basic. The unprotonated nitrogen atom of the pyridyl ring can be protonated by an acid, either organic or inorganic. Representative inorganic acids are hydrochloric, nitric, hydrobromic, sulfuric, sulfamic and phosphoric. Representative organic acids are acetic, trifluoroacetic, benzoic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, phenylphosphonic and organophosphonic. The salts so formed are also fungicidal.

EXAMPLE 1 Preparation of N-(2-Methoxy-5-pyridyl)-cyclopropane carboxamide

5-Amino-2-methoxy pyridine (12.4 grams, 0.10 mole), 10 milliliter (ml) of pyridine were mixed together in 200 ml dichloromethane in a reaction flask. 9.1 ml (0.10 mole) of cyclopropane carboxylic acid chloride was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was washed with 200 ml of 5% sodium hydroxide and 100 ml of water. The resulting organic phase was separated and dried over magnesium sulfate crystals. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 grams, after drying. The product was identified by IR and NMR as the title compound, having a melting point of 130°-131° C.

EXAMPLE 2 Preparation of N-(2-Methoxy-5-pyridyl)-bis-(cyclopropane carbox)-imide

0.6 Grams sodium hydride (NaH) was mixed with 50 ml THF in a reaction vessel. 3.6 g (0.02M) of the product of Example 1 was mixed (with stirring) to the THF/NaH mixture. After 15 minutes of continued stirring, 1.82 ml of cyclopropane carboxylic acid chloride was added. The reaction was exothermic and the temperature rose to 30° C. Stirring was continued for one hour, after which the reaction mixture was diluted with 200 ml hexane and washed three times with 150 ml portions of water, dried over MgSO₄ and evaporated on a rotary evaporator, yielding a solid which was washed with pentane and then hexane:ether (3:10) filtered through florisil and evaporated to yield 0.4 g of a solid having a melting point of 107°-114° C., which was identified by nuclear magnetic resonance (nmr) spectroscopy as the title compound. This compound will be known as Compound 1.

EXAMPLE 3 Preparation of O-Ethyl-N-(2-Methoxy-5-pyridyl-cyclopropanecarboxyl) oxamate

In a 500 ml flask, 19.2 g (0.1M) of the compound of Example 1 and 200 ml of benzene were mixed under a nitrogen atmosphere and chilled to 5° C. Thirteen grams (0.12M) chlorotrimethyl silane at 5° C. was mixed with 12.3 g (0.12M) triethylamine in 25 ml benzene in an addition funnel and chilled to 5° C. The mixture in the addition funnel was slowly added to the mixture in the 500 ml flask over 0.5 hour and the reaction mixture held at 5° C. to 10° C. for another 0.5 hour. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours and filtered. The filter cake was washed twice with 100 ml portions of benzene and dried on a rotary evaporator. The product can be distilled with the boiling point being 118.0°-120.0° C./0.5 mmHg. The product was a clear viscous liquid which solidified on standing. The product was identified as N-(2-methoxy-5-pyridyl)-cyclopropanecarboxy-N-trimethylsilane amide.

In a 100 ml round-bottom flask, 2.64 g (0.01M) of the above prepared silane amide was mixed with 25 ml dichloromethane and 1.25 ml (0.011M) ethyl oxalyl chloride and stirred for 0.5 hour to complete the reaction. The reaction mixture was filtered through dicalite and the filter cake was stripped on a rotary evaporator, washed with 25 ml hexane, filtered and vacuum dried. 2.39 grams (81% yield) of a solid having a melting point of 69°-71° C. was recovered. The product was identified as the title compound by infrared, nuclear magnetic resonance and mass spectroscopy. This compound will be known as Compound No. 3.

Representative compounds of this invention and their properties are shown in Table I.

                                      TABLE I                                      __________________________________________________________________________      ##STR8##                                                                                                     Physical Properties                             Cmpd.                          n.sub.D.sup.30 or                               No. R        R.sub.1                                                                             R.sub.2                                                                             R.sub.3                                                                            X Y melting point °C.                        __________________________________________________________________________          ##STR9##                                                                               --   OCH.sub.3                                                                           H   O O 107.0-114.0                                     2   H        --   OCH.sub.3                                                                           H   O O 1.5630                                          3                                                                                   ##STR10##                                                                              C.sub.2 H.sub.5                                                                     OCH.sub.3                                                                           H   O O 69.0-71.0                                       4                                                                                   ##STR11##                                                                              C.sub.2 H.sub.5                                                                     OCH.sub.3                                                                           H   O O 95.0-98.0                                       5                                                                                   ##STR12##                                                                              C.sub.2 H.sub.5                                                                     OCH.sub.3                                                                           H   O O semi-solid                                      6   SCH.sub.3                                                                               --   OCH.sub.3                                                                           H   O O 137.0-138.0                                     7   OCH.sub.3                                                                               --   OCH.sub.3                                                                           H   O O 120.0-122.0                                     8   CH.sub.3 --   OCH.sub.3                                                                           H   O O                                                 9                                                                                   ##STR13##                                                                              --   OCH.sub.3                                                                           H   O O                                                 10                                                                                  ##STR14##                                                                              --   OCH.sub.3                                                                           H   O O 95.0-100.0                                      11                                                                                  ##STR15##                                                                              --   OCH.sub.3                                                                           CH.sub.3                                                                           O O                                                 12  the hydrochloric acid salt of compound 10                                                                 125 (dec)                                       13                                                                                  ##STR16##    Cl   H   O O 100.0-105.0                                     __________________________________________________________________________

EXAMPLE 3 Mole Equivalent Preventative Spray Evaluation Procedures

Barley Powdery Mildew (BPM)

Northrup King Sunbar 401 barley seed is planted (12 seeds/2" pot) in a sandy-loam soil seven days prior to testing. The test compound is diluted in a 50/50 acetone/water solution to produce concentrations decreasing from 0.004 molar. Twelve ml of test solution are sprayed onto the barley plants with atomizing sprayers.

Twenty-four hours later, test plants are placed in an inoculation box equipped with a circulating fan. Barley plants with heavily sporulating Erysiphe gramins lesions are placed in front of the fan to dislodge and distribute the spores. After two minutes the fan is shut off and the chamber is left closed five minutes for the spores to settle. Inoculated plants are then placed on an automatic sub-irrigation greenhouse bench.

Results are recorded seven days following inoculation as percent disease control based on the percent reduction in lesion area as compared to the untreated control plants. Compound concentrations which provide 90% disease control (CO 90) are determined from dosage/dilution curves.

Leaf Rust (LR)

Seven seeds of Anza wheat are planted in 2" pots in a sandy-loam soil 12 days prior to testing. The compound to be tested is diluted with a 50/50 acetone/water solution to produce concentrations decreasing from 0.004 molar. Twelve ml of test solution are sprayed onto the wheat plants with an atomizing sprayer.

A suspension of Puccinia recondita urediospores is prepared by vacuuming spores from wheat leaves with ureida pustules and suspending 10⁵ spores/ml in deionized water plus 0.5% Tween® 20 (polyoxyethylene sorbitan monolaurate). Plants are inoculated 24 hours after treatment by spraying with the spore suspension to runoff, allowing it to dry on the leaves, respraying to runoff, and then placing the plants into a dark mist chamber. Following 48 hours in the mist, plants are moved to a subirrigation greenhouse bench.

Results are recorded ten days following inoculation as percent disease control based on the percent reduction in lesion area as compared to the untreated control plants. Compound concentrations which provide 90% disease control (EC 90) are determined from dosage/dilution curves.

Botrytis Bud Blight (BB)

Two white rose petals are placed in a petri dish lined with wet filter paper. The compound to be tested is diluted with a 50/50 acetone/water solution to produce concentrations decreasing from 0.004 molar. One half ml of test solution is atomized onto the petals, and allowed to dry.

Inoculum is prepared by adding a 5 mm plug from a two-week old Botrytis cineria culture grown on Elliot's V-8 agar, to 10 ml sterile distilled water plus 0.5% grape juice. A 20 ul drop of this inoculum suspension is placed on each petal. Petri dishes with inoculated petals are stored in sealed plastic boxes to maintain saturated humidity.

Results are read four days following inoculation as a percent reduction in necrotic area compared to the acetone/water controls. Compound concentrations which provide 90% disease control (EC 90) are determined from dosage/dilution curves.

The results are presented in Table II as an approximate EC 90 in parts per million. The entry (750) indicates partial control at 750 ppm.

                  TABLE II                                                         ______________________________________                                         Cmpd. No.  BPM           LR      BB                                            ______________________________________                                         1          >750          >750    30                                            2          >750          >750    70                                            3          200            600    30                                            4          750            750    30                                            5          750           >750    80                                            6          --            --      30                                            7          --            --      250                                           8          --            --      30                                            9          --            --      20                                            10         --            --      40                                            11         --            --      80                                            12         --            --      80                                            13         --            --      750                                           ______________________________________                                    

EXAMPLE 4 Curative Spray Evaluation Procedures

Leaf Rust (LR)

Seven seeds of Anza wheat are planted in 2" pots in a sandy loam soil 12 days prior to testing. A suspension of Puccinia recondita urediospores is prepared by vacuuming spores from wheat leaves with uredia pustules and suspending 10⁵ spores/ml in deionized water plus 0.5% Tween-20 (polyoxyethylene sorbitan monolaurate). Plants are inoculated by spraying with the spore suspension to runoff, allowing it to dry on the leaves, respraying to runoff, and then placing the plants into a mist chamber. Following 48 hours in the mist, plants are moved to a subirrigation greenhouse bench.

The compound to be tested is diluted in a 50/50 acetone/water solution to produce concentrations decreasing from 0.075%. Fifty hours following inoculation, the plants are placed on a rotating turntable and sprayed with the test solution to near runoff with atomizing nozzles. (Time of inoculation is defined as when plants are placed into the mist chamber).

Results are recorded ten days following inoculation as percent disease control based on the percent reduction in lesion area as compared to the untreated control plants.

                  TABLE III                                                        ______________________________________                                                Cmpd. No.                                                                              LR                                                              ______________________________________                                                1       100                                                                    2       100                                                                    3       100                                                                    4       100                                                                    5       100                                                             ______________________________________                                    

The compounds of this invention are particularly effective against Botrytis bud blight and are particularly effective as preventative foliar sprays and curative foliar sprays when compared to standard commercial compounds used as Botrytis preventative and curative sprays. Fungi on which the compounds of the present invention are particularly effective are as follows: Erysiphe graminis; Puccinia graminis; and Piricularia oryzae.

The compounds of the present invention are useful as fungicides, especially as preventative or curative fungicides, and can be applied in a variety of ways at various concentrations. In general, these compounds and formulations of these compounds can be applied directly to the crop foliage, the soil in which the crop is growing or in the irrigation water for the crop or soil. In practice, the compounds herein defined are formulated into fungicidal compositions, by admixture, in fungicidally effective amounts, with the adjuvants and carriers normally employed for facilitating the dispersion of active ingredients for agricultural applications, recognizing the fact that the formulation and mode of application of a toxicant may affect the activity of the materials in a given application. Thus, these active fungicidal compounds may be formulated as wettable powders, as emulsifiable concentrates, as powdery dusts, as solutions or as any of several other known types of formulations, depending upon the desired mode of application. Preferred formulations for preventative or curative fungicidal applications are wettable powders and emulsifiable concentrates. These formulations may contain as little as about 0.1% to as much as about 95% or more by weight of active ingredient. A fungicidally effective amount depends upon the nature of the seeds or plants to be treated and the rate of application varies from about 0.05 to approximately 25 pounds per acre, preferably from about 0.1 to about 10 pounds per acre.

Wettable powders are in the form of finely divided particles which disperse readily in water or other dispersants. The wettable powder is ultimately applied to the soil or plants either as a dry dust or as a dispersion in water or other liquid. Typical carriers for wettable powders include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic diluents. Wettable powders normally are prepared to contain about 5% to about 95% of the active ingredient and usually also contain a small amount of wetting, dispersing, or emulsifying agent to facilitate wetting and dispersion.

Dry flowables or water dispersible granules are agglomerated wettable powders made by either pan granulation or by fluidized bed. The dry flowable is ultimately applied to the soil or plants as a dispersion in water or other liquid. These granules are dust-free and free flowing when dry and yet upon dilution in water, form homogeneous dispersions. Typical carriers for dry flowables include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic diluents. The dry flowables normally are prepared to contain from about 5% to about 95% of the active ingredient and usually contain a small amount of wetting, dispersing or emulsifying agent to facilitate wetting and dispersion.

Emulsifiable concentrates are homogeneous liquid compositions which are dispersible in water or other dispersant, and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphtha, isophorone and other non-volatile organic solvents. For fungicidal application, these concentrates are dispersed in water or other liquid carrier and normally applied as a spray to the area to be treated. The percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises about 0.1% to 95% of active ingredient by weight of the fungicidal composition.

Typical wetting, dispersing or emulsifying agents used in agricultural formulations include, for example, the alkyl and alkylaryl sulfonates and sulfates and their sodium salts; polyhydroxy alcohols; and other types of surface-active agents, many of which are available in commerce. The surface-active agent, when used, normally comprises from 0.1% to 15% by weight of the fungicidal composition.

Dusts, which are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours and other organic and inorganic solids which act as dispersants and carriers for the toxicant, are useful formulations for many applications.

Pastes, which are homogeneous suspensions of a finely divided solid toxicant in a liquid carrier such as water or oil, are employed for specific purposes. These formulations normally contain about 5% to about 95% of active ingredient by weight, and may also contain small amounts of a wetting, dispersing or emulsifying agent to facilitate dispersion. For application, the pastes are normally diluted and applied as a spray to the area to be affected.

    ______________________________________                                         EXAMPLES OF TYPICAL FORMULATIONS                                               Ingredient           Weight %                                                  ______________________________________                                         Oil                                                                            Compound 1           1                                                         Oil solvent-heavy aromatic naphtha                                                                  99                                                        Total                100                                                       Emulsifiable Concentrate                                                       Compound 2           50                                                        Kerosene             45                                                        Emulsifying agent (mixture of long                                                                  5                                                         chain ethoxylated polyethers with                                              long chain sulfonate)                                                          Total                100                                                       Emulsifiable Concentrate                                                       Compound 3           90                                                        Kerosene             5                                                         Emulsifying agent (mixture of long                                                                  5                                                         chain ethoxylated polyethers with                                              long chain sulfonate)                                                          Total                100%                                                      ______________________________________                                          Dusts and/or Powders                                                                         Wt. %      Wt. %   Wt. %                                        ______________________________________                                         Compound 4     0.5        50.0    90.0                                         Attapulgite Clay Powder                                                                       93.5       44.0    4.0                                          Sodium lignin sulfonate                                                                       5.0        5.0     5.0                                          Sodium dioctyl sulfosuccinate                                                                 1.0        1.0     1.0                                          Total          100.0      100.0   100.0                                        ______________________________________                                    

Other useful formulations for fungicidal applications include simple solutions of the active ingredient in a dispersant in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents. Pressurized sprays, typically aerosols, wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low boiling dispersant solvent carrier, such as the Freons, may also be used.

The fungicidal compositions of this invention are applied to the plants in the conventional manner. Thus, the dust and liquid compositions can be applied to the plant by the use of power-dusters, boom and hand sprayers and spray dusters. The compositions can also be applied from airplanes as a dust or a spray because they are effective in low dosages. 

We claim:
 1. A compound having the structural formula ##STR17## wherein R is selected from the group consisting of oxalyl, OR₁, SR₁ and ##STR18## wherein n is 0-2, R₁ is C₁ -C₄ alkyl, R₂ is selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁ -C₃ haloalkoxy, R₃ is selected from the group consisting of hydrogen and methyl, X is --O or --S and Y is --O or --S; or a fungicidally acceptable organic or inorganic salt thereof.
 2. The compound of claim 1 wherein R is ##STR19## and R₁ is --C₂ H₅, R₂ is --OCH₃, X is O, Y is O and R₃ is --H.
 3. The compound of claim 1 wherein R is ##STR20## R₁ is --C2H₅, R₂ is --OCH₃, X is O, Y is O and R₃ is --H.
 4. The compound of claim 1 wherein R is ##STR21## R₁ is C₂ H₅, R₂ is --OCH₃, X is O, Y is O and R₃ is --H.
 5. A fungicidal composition comprising a fungicidally effective amount of a compound having the structural formula ##STR22## wherein R is selected from the group consisting of oxalyl, OR₁, SR₁ and ##STR23## wherein n is 0-2, R₁ is C₁ -C₄ alkyl, R₂ is selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁ -C₃ haloalkoxy, R₃ is selected from the group consisting of hydrogen and methyl, X is --O or --S and Y is --O or --S; or a fungicidally acceptable organic or inorganic salt thereof, and an inert diluent carrier therefor.
 6. The method of controlling fungi comprising applying to the area where control is desired, a fungicidally effective amount of a compound having the formula ##STR24## wherein R is selected from the group consisting of oxalyl, OR₁, SR₁ and ##STR25## wherein n is 0-2, R₁ is C₁ -C₄ alkyl, R₂ is selected from the group consisting of halogen, C₁ -C₃ alkoxy and C₁ -C₃ haloalkoxy, R₃ is selected from the group consisting of hydrogen and methyl, X is --O or --S and Y is --O or --S; or a fungicidally acceptable organic or inorganic salt thereof.
 7. The compound of claim 6 wherein R is ##STR26## and R₁ is --C₂ H₅, R₂ is --OCH₃, X is O, Y is O and R₃ is --H.
 8. The compound of claim 6 wherein R is ##STR27## R₁ is --C₂ H₅, R₂ is --OCH₃, X is O, Y is O and R₃ is --H.
 9. The compound of claim 6 wherein R is ##STR28## R₁ is --C₂ H₅, R₂ is --OCH₃, X is O, Y is O and R₃ is --H. 